Potassium (K+) channels are a diverse class of ion channels and have several critical roles in cell function. One role is in neurons, where K+ channels are responsible, in part, for determining cell excitability by contributing to membrane repolarization following depolarization, resting membrane potential, and regulation of neurotransmitter release. The M-current, measured by electrophysiology recording methods and by pharmacology, has been described as a dominant conductance in controlling neuronal excitability. Pharmacological activation or suppression of M currents by small molecules could have profound effects in controlling neuronal excitability. Recently, Wang reported that co-assembly of the KCNQ2 and KCNQ3 potassium channels underlies the native M-current in neurons (Wang et al., Science 1998, 282, 1890–1893).
Compounds that block KCNQ channels and M current, including linopirdine and XE-991, demonstrate cognition enhancing effects. The compounds act by increasing the stimulus-evoked release of a number of neurotransmitters in the central nervous system. See Wang et al. Science 1998, 282, 1890; Lamas Eur. J. Neurosci. 1997, 9, 607; Schnee and Brown J. Pharmacol. Exp. Ther. 1998, 286, 709; Zaczek et al. J. Pharmacol Exp. Ther. 1998, 285, 724 and references cited by these papers.
At the time linopirdine and XE-991 were discovered, they were not known to be KCNQ blockers and were not optimized for KCNQ inhibition or selectivity. Thus, potent and selective KCNQ blockers offer a promising opportunity for treating impairments of memory or cognition.
2-Amino-5-carboxamidopyrimidines have been disclosed. See Suto et al. U.S. Pat. No. 5,811,428. Nothing in this reference discloses or suggests the novel compounds of this application.